scholarly journals Modeling Brain Somatic Mosaicism With Cerebral Organoids, Including a Note on Mutant Microglia

2019 ◽  
Vol 12 ◽  
Author(s):  
Bert M. Verheijen
Keyword(s):  
Nervous System ◽  
System Development ◽  
Somatic Mosaicism ◽  
3D Culture ◽  
3D Cell Culture ◽  
Nervous System Development ◽  
Genomic Diversity ◽  
Human Organ ◽  
Development And Aging

The brain is a genomic mosaic. Cell-to-cell genomic differences, which are the result of somatic mutations during development and aging, contribute to cellular diversity in the nervous system. This genomic diversity has important implications for nervous system development, function, and disease. Brain somatic mosaicism might contribute to individualized behavioral phenotypes and has been associated with several neuropsychiatric and neurodegenerative disorders. Therefore, understanding the causes and consequences of somatic mosaicism in neural circuits is of great interest. Recent advances in 3D cell culture technology have provided new means to study human organ development and various human pathologies in vitro. Cerebral organoids (“mini-brains”) are pluripotent stem cell-derived 3D culture systems that recapitulate, to some extent, the developmental processes and organization of the developing human brain. Here, I discuss the application of these neural organoids for modeling brain somatic mosaicism in a lab dish. Special emphasis is given to the potential role of microglial mutations in the pathogenesis of neurodegenerative diseases.

scholarly journals Drosophila Stathmin: A Microtubule-destabilizing Factor Involved in Nervous System Formation

2002 ◽  
Vol 13 (2) ◽  
pp. 698-710 ◽  
Author(s):  
Sylvie Ozon ◽  
Antoine Guichet ◽  
Olivier Gavet ◽  
Siegfried Roth ◽  
André Sobel
Keyword(s):  
Nervous System ◽  
System Development ◽  
Nervous System Development ◽  
Microtubule Assembly ◽  
Nervous Systems ◽  
Germ Cell Migration ◽  
Numerous Cell ◽  
First Time

Stathmin is a ubiquitous regulatory phosphoprotein, the generic element of a family of neural phosphoproteins in vertebrates that possess the capacity to bind tubulin and interfere with microtubule dynamics. Although stathmin and the other proteins of the family have been associated with numerous cell regulations, their biological roles remain elusive, as in particular inactivation of the stathmin gene in the mouse resulted in no clear deleterious phenotype. We identified stathmin phosphoproteins inDrosophila, encoded by a unique gene sharing the intron/exon structure of the vertebrate stathmin andstathmin family genes. They interfere with microtubule assembly in vitro, and in vivo when expressed in HeLa cells. Drosophila stathmin expression is regulated during embryogenesis: it is high in the migrating germ cells and in the central and peripheral nervous systems, a pattern resembling that of mammalian stathmin. Furthermore, RNA interference inactivation ofDrosophila stathmin expression resulted in germ cell migration arrest at stage 14. It also induced important anomalies in nervous system development, such as loss of commissures and longitudinal connectives in the ventral cord, or abnormal chordotonal neuron organization. In conclusion, a single Drosophilagene encodes phosphoproteins homologous to the entire vertebrate stathmin family. We demonstrate for the first time their direct involvement in major biological processes such as development of the reproductive and nervous systems.

scholarly journals Regulation of miRNAs during Retinoic Acid-Induced Regeneration of a Molluscan Central Nervous System

2018 ◽  
Author(s):  
Sarah E. Walker ◽  
Gaynor E. Spencer ◽  
Alexsandr Necakov ◽  
Robert L. Carlone
Keyword(s):  
Nervous System ◽  
Retinoic Acid ◽  
Lymnaea Stagnalis ◽  
System Development ◽  
Growth Cones ◽  
Nervous System Development ◽  
Biologically Active ◽  
Neuronal Outgrowth ◽  
First Time

Retinoic acid (RA) is the biologically active metabolite of vitamin A,and has become a well-established factor that induces neurite outgrowth and regeneration in both vertebrates and invertebrates. However, the underlying regulatory mechanisms that may mediate RA-induced neurite sprouting remain unclear. In the past decade, microRNAs have emerged as important regulators of nervous system development and regeneration, and have been shown to contribute to processes such as neurite sprouting. However, few studies have demonstrated the role of miRNAs in RA-induced neurite sprouting. By R-Seq analysis, we identify 482 miRNAs in the regenerating CNS of the mollusc Lymnaea stagnalis, 219 of which represent potentially novel miRNAs. Of the remaining conserved miRNAs, 38 show a statistically significant up or downregulation in regenerating CNS as a result of RA treatment. We further characterized the expression of one neuronally-enriched miRNA upregulated by RA, miR-124. We demonstrate for the first time that miR-124 is expressed within the cell bodies and neurites of regenerating motorneurons. Moreover, we identify miR-124 expression within the growth cones of cultured ciliary motorneurons (Pedal A), whereas expression from the growth cones of another class of respiratory motorneurons (RPA) was absent in vitro. These findings support our hypothesis miRNAs are important regulators of retinoic acid induced neuronal outgrowth and regeneration in regeneration-competent species.

Neurons from stem cells: Implications for understanding nervous system development and repair

2000 ◽  
Vol 78 (5) ◽  
pp. 613-628 ◽  
Author(s):  
Fiona C Mansergh ◽  
Michael A Wride ◽  
Derrick E Rancourt
Keyword(s):  
Stem Cells ◽  
Nervous System ◽  
Neural Differentiation ◽  
System Development ◽  
Nervous System Development ◽  
Neural Cells ◽  
Ageing Population ◽  
Bioinformatic Tools ◽  
Functional Characterisation

Neurodegenerative diseases cost the economies of the developed world billions of dollars per annum. Given ageing population profiles and the increasing extent of this problem, there has been a surge of interest in neural stem cells and in neural differentiation protocols that yield neural cells for therapeutic transplantation. Due to the oncogenic potential of stem cells a better characterisation of neural differentiation, including the identification of new neurotrophic factors, is required. Stem cell cultures undergoing synchronous in vitro neural differentiation provide a valuable resource for gene discovery. Novel tools such as microarrays promise to yield information regarding gene expression in stem cells. With the completion of the yeast, C. elegans, Drosophila, human, and mouse genome projects, the functional characterisation of genes using genetic and bioinformatic tools will aid in the identification of important regulators of neural differentiation.Key words: neural differentiation, neural precursor cell, brain repair, central nervous system repair, CNS.

scholarly journals Different Subcellular Localization of ALCAM Molecules in Neuroblastoma: Association with Relapse

2010 ◽  
Vol 32 (1-2) ◽  
pp. 77-86
Author(s):  
Maria Valeria Corrias ◽  
Claudio Gambini ◽  
Andrea Gregorio ◽  
Michela Croce ◽  
Gaia Barisione ◽  
...  
Keyword(s):  
Nervous System ◽  
Subcellular Localization ◽  
Cell Lines ◽  
System Development ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Nervous System Development ◽  
Primary Tumors ◽  
Neuroblastoma Cell Lines

Background: The Activated Leukocyte Cell Adhesion Molecule (ALCAM/CD), involved in nervous system development, has been linked to tumor progression and metastasis in several tumors. No information is available on ALCAM expression in neuroblastoma, a childhood neoplasia originating from the sympathetic nervous system.Methods: ALCAM expression was analysed by immunofluorescence and immunohistochemistry on differentiated neuroblastoma cell lines and on archival specimens of stroma-poor, not MYCN amplified, resectable neuroblastoma tumors, respectively.Results: ALCAM is variously expressed in neuroblastoma cell lines, is shed by metalloproteases and is cleaved by ADAM17/TACE in vitro. ALCAM is expressed in neuroblastoma primary tumors with diverse patterns of subcellular localization and is highly expressed in the neuropil area in a subgroup of cases. Tumor specimens showing high expression of ALCAM at the membrane of the neuroblast body or low levels in the neuropil area are associated with relapse (P = 0.044 and P < 0.0001, respectively). In vitro differentiated neuroblastoma cells show strong ALCAM expression on neurites, suggesting that ALCAM expression in the neuropil is related to a differentiated phenotype.Conclusions: Assessment of ALCAM localization by immunohistochemistry may help to identify patients who, in the absence of negative prognostic factors, are at risk of relapse and require a more careful follow-up.

scholarly journals High-throughput 3D screening for differentiation of hPSC-derived cell therapy candidates

2020 ◽  
Vol 6 (32) ◽  
pp. eaaz1457
Author(s):  
Riya Muckom ◽  
Xiaoping Bao ◽  
Eric Tran ◽  
Evelyn Chen ◽  
Abirami Murugappan ◽  
...  
Keyword(s):  
Cell Therapy ◽  
High Throughput ◽  
System Development ◽  
Three Dimensional ◽  
3D Culture ◽  
3D Cell Culture ◽  
Culture Conditions ◽  
Nervous System Development ◽  
Oligodendrocyte Progenitor Cells ◽  
Cell Therapies

The emergence of several cell therapy candidates in the clinic is an encouraging sign for human diseases/disorders that currently have no effective treatment; however, scalable production of these cell therapies has become a bottleneck. To overcome this barrier, three-dimensional (3D) cell culture strategies have been considered for enhanced cell production. Here, we demonstrate a high-throughput 3D culture platform used to systematically screen 1200 culture conditions with varying doses, durations, dynamics, and combinations of signaling cues to derive oligodendrocyte progenitor cells and midbrain dopaminergic neurons from human pluripotent stem cells (hPSCs). Statistical models of the robust dataset reveal previously unidentified patterns about cell competence to Wnt, retinoic acid, and sonic hedgehog signals, and their interactions, which may offer insights into the combinatorial roles these signals play in human central nervous system development. These insights can be harnessed to optimize production of hPSC-derived cell replacement therapies for a range of neurological indications.

scholarly journals Role of miRNA-mRNA Interaction in Neural Stem Cell Differentiation of Induced Pluripotent Stem Cells

2020 ◽  
Vol 21 (19) ◽  
pp. 6980
Author(s):  
Satish Kumar ◽  
Joanne E. Curran ◽  
Erica DeLeon ◽  
Ana C. Leandro ◽  
Tom E. Howard ◽  
...  
Keyword(s):  
Nervous System ◽  
Synapse Formation ◽  
System Development ◽  
Target Prediction ◽  
Stem Cell Differentiation ◽  
Nervous System Development ◽  
P Value ◽  
Protein Coding ◽  
Human Ipscs

miRNA regulates the expression of protein coding genes and plays a regulatory role in human development and disease. The human iPSCs and their differentiated progenies provide a unique opportunity to identify these miRNA-mediated regulatory mechanisms. To identify miRNA–mRNA regulatory interactions in human nervous system development, well characterized NSCs were differentiated from six validated iPSC lines and analyzed for differentially expressed (DE) miRNome and transcriptome by RNA sequencing. Following the criteria, moderated t statistics, FDR-corrected p-value ≤ 0.05 and fold change—absolute (FC-abs) ≥2.0, 51 miRNAs and 4033 mRNAs were found to be significantly DE between iPSCs and NSCs. The miRNA target prediction analysis identified 513 interactions between 30 miRNA families (mapped to 51 DE miRNAs) and 456 DE mRNAs that were paradoxically oppositely expressed. These 513 interactions were highly enriched in nervous system development functions (154 mRNAs; FDR-adjusted p-value range: 8.06 × 10−15–1.44 × 10−4). Furthermore, we have shown that the upregulated miR-10a-5p, miR-30c-5p, miR23-3p, miR130a-3p and miR-17-5p miRNA families were predicted to down-regulate several genes associated with the differentiation of neurons, neurite outgrowth and synapse formation, suggesting their role in promoting the self-renewal of undifferentiated NSCs. This study also provides a comprehensive characterization of iPSC-generated NSCs as dorsal neuroepithelium, important for their potential use in in vitro modeling of human brain development and disease.

scholarly journals The Monocarboxylate Transporter 8 Linked to Human Psychomotor Retardation Is Highly Expressed in Thyroid Hormone-Sensitive Neuron Populations

Endocrinology ◽  
2005 ◽  
Vol 146 (4) ◽  
pp. 1701-1706 ◽  
Author(s):  
Heike Heuer ◽  
Michael K. Maier ◽  
Sandra Iden ◽  
Jens Mittag ◽  
Edith C. H. Friesema ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Thyroid Hormone ◽  
System Development ◽  
Perinatal Period ◽  
Psychomotor Retardation ◽  
Nervous System Development ◽  
Monocarboxylate Transporter ◽  
Target Cells

Abstract Recent genetic analysis in several patients presenting a severe form of X-linked psychomotor retardation combined with abnormal thyroid hormone (TH) levels have revealed mutations or deletions in the gene of the monocarboxylate transporter 8 (MCT8). Because in vitro MCT8 functions as a TH transporter, the complex clinical picture of these patients indicated an important role for MCT8 in TH-dependent processes of brain development. To provide a clue to the cellular function of MCT8 in brain, we studied the expression of MCT8 mRNA in the murine central nervous system by in situ hybridization histochemistry. In addition to the choroid plexus structures, the highest transcript levels were found in neo- and allocortical regions (e.g. olfactory bulb, cerebral cortex, hippocampus, and amygdala), moderate signal intensities in striatum and cerebellum, and low levels in a few neuroendocrine nuclei. Colocalization studies revealed that MCT8 is predominantly expressed in neurons. Together with the spatiotemporal expression pattern of MCT8 during the perinatal period, these results strongly indicate that MCT8 plays an important role for proper central nervous system development by transporting TH into neurons as its main target cells.

scholarly journals Identification and Characterization of microRNAs during Retinoic Acid-Induced Regeneration of a Molluscan Central Nervous System

2018 ◽  
Vol 19 (9) ◽  
pp. 2741 ◽  
Author(s):  
Sarah Walker ◽  
Gaynor Spencer ◽  
Aleksandar Necakov ◽  
Robert Carlone
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Retinoic Acid ◽  
Lymnaea Stagnalis ◽  
System Development ◽  
Growth Cones ◽  
Nervous System Development ◽  
Biologically Active ◽  
Sequencing Analysis

Retinoic acid (RA) is the biologically active metabolite of vitamin A and has become a well-established factor that induces neurite outgrowth and regeneration in both vertebrates and invertebrates. However, the underlying regulatory mechanisms that may mediate RA-induced neurite sprouting remain unclear. In the past decade, microRNAs have emerged as important regulators of nervous system development and regeneration, and have been shown to contribute to processes such as neurite sprouting. However, few studies have demonstrated the role of miRNAs in RA-induced neurite sprouting. By miRNA sequencing analysis, we identify 482 miRNAs in the regenerating central nervous system (CNS) of the mollusc Lymnaea stagnalis, 219 of which represent potentially novel miRNAs. Of the remaining conserved miRNAs, 38 show a statistically significant up- or downregulation in regenerating CNS as a result of RA treatment. We further characterized the expression of one neuronally-enriched miRNA upregulated by RA, miR-124. We demonstrate, for the first time, that miR-124 is expressed within the cell bodies and neurites of regenerating motorneurons. Moreover, we identify miR-124 expression within the growth cones of cultured ciliary motorneurons (pedal A), whereas expression in the growth cones of another class of respiratory motorneurons (right parietal A) was absent in vitro. These findings support our hypothesis that miRNAs are important regulators of retinoic acid-induced neuronal outgrowth and regeneration in regeneration-competent species.

Evolvability of the actin cytoskeleton in oligodendrocytes during central nervous system development and aging

2018 ◽  
Vol 76 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Ana Isabel Seixas ◽  
Maria Manuela Azevedo ◽  
Joana Paes de Faria ◽  
Diogo Fernandes ◽  
Inês Mendes Pinto ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Actin Cytoskeleton ◽  
System Development ◽  
Nervous System Development ◽  
Central Nervous System Development ◽  
Development And Aging
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